Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a progressive neuromuscular disease that weakens and eventually destroys motor neurons (components of the nervous system that connect the brain with the skeletal muscles). Skeletal muscles are involved with voluntary movements, such as walking and talking. The motor neurons transmit the command to move from the brain to the skeletal muscles, which respond by contracting.
A person with ALS usually presents with problems in dexterity or gait resulting from muscle weakness, or with difficulty speaking or swallowing. Sphincter control, sensory function, intellectual ability, and skin integrity are preserved. Patients become paralyzed and often require ventilation and surgery to provide a new opening in the stomach (gastrostomy). Loss of respiratory function is ultimately the cause of death.
ALS is an adult onset neurodegenerative disease in which two percent of all cases are caused by mutations in the gene encoding copper/zinc superoxide dismutase (SOD-1). Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O'Regan, J. P., and Deng, H. X. (1993) Nature 362, 59-62. More than 100 mutations distributed throughout the structure of the protein introduce a toxic gain of function that decreases protein solubility, leading to aggregation and the formation of both detergent-insoluble SOD-1 and inclusions that are a histopathological hallmark of ALS. Shinder, G. A., Lacourse, M. C., Minotti, S., and Durham, H. D. (2001) J. Biol. Chem. 276, 12791-12796; Johnston, J. A., Dalton, M. J., Gurney, M. E., and Kopito, R. R. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 12571-12576; Shibata, N., Asayama, K., Hirano, A., and Kobayashi, M. (1996) Dev. Neurosci. 18, 492-498; Bruijn, L. I., Becher, M. W., Lee, M. K., Anderson, K. L., Jenkins, N. A., Copeland, N. G., Sisodia, S. S., Rothstein, J. D., Borchelt, D. R., Price, D. L., and Cleveland, D. W. (1997) Neuron 18, 327-338; Durham, H. D., Roy, J., Dong, L., and Figlewicz, D. A. (1997) J. Neuropathol. Exp. Neurol. 56, 523-530; Kato, S., Horiuchi, S., Liu, J., Cleveland, D. W., Shibata, N., Nakashima, K., Nagai, R., Hirano, A., Takikawa, M., Kato, M., Nakano, I., and Ohama, E. (2000) Acta Neuropathol. (Berl.) 100, 490-505; Aoki, M., Kato, S., Nagai, M., and Itoyama, Y. (2005) Neuropathology 25, 365-370.
It is known that a portion of fALS is linked to a genetic defect on chromosome 21. This gene codes for an enzyme called superoxide dismutase (SOD-1), an antioxidant that protects motor neurons from free radical damage. The nature of the toxic gain of function imparted by familial ALS (fALS)-causing SOD-1 mutations is not completely understood (reviewed in Shaw, B. F., and Valentine, J. S. (2007) Trends Biochem. Sci 32, 78-85). These mutations do, however, provide evidence that diverse and relatively minor changes in SOD-1 primary structure can cause fALS. Approximately ninety percent of ALS is sporadic, and it is plausible that post-translational modification of wild-type proteins affects structural changes analogous to those caused by point mutation. Bredesen, D. E., Ellerby, L. M., Hart, P. J., Wiedau-Pazos, M., and Valentine, J. S. (1997) Ann. Neurol. 42, 135-137. Indeed, Lewy body-like inclusions in sporadic ALS are immunoreactive with antibodies to SOD-1. Shibata, N., Hirano, A., Kobayashi, M., Siddique, T., Deng, H. X., Hung, W. Y., Kato, T., and Asayama, K. (1996) J. Neuropathol. Exp. Neurol. 55, 481-490; Shibata, N., Hirano, A., Kobayashi, M., Sasaki, S., Kato, T., Matsumoto, S., Shiozawa, Z., Komori, T., Ikemoto, A., and Umahara, T. (1994) Neurosci. Lett. 179, 149-152; Chou, S. M., Wang, H. S., and Komai, K. (1996) J. Chem. Neuroanat. 10, 249-258. It has also been demonstrated that oxidative post-translational modification of SOD-1 occurs in vivo with aging and in association with the fALS, Parkinson, and Alzheimer neurodegenerative diseases. Takata, I., Kawamura, N., Myint, T., Miyazawa, N., Suzuki, K., Maruyama, N., Mino, M., and Taniguchi, N. (1996) Biochem. Biophys. Res. Commun. 219, 243-248; Kato, S., Nakashima, K., Horiuchi, S., Nagai, R., Cleveland, D. W., Liu, J., Hirano, A., Takikawa, M., Kato, M., Nakano, I., Sakoda, S., Asayama, K., and Ohama, E. (2001) Neuropathology 21, 67-81; Shibata, N., Hirano, A., Kato, S., Nagai, R., Horiuchi, S., Komori, T., Umahara, T., Asayama, K., and Kobayashi, M. (1999) Acta Neuropathol. (Berl.) 97, 240-246; Kato, S., Horiuchi, S., Nakashima, K., Hirano, A., Shibata, N., Nakano, I., Saito, M., Kato, M., Asayama, K., and Ohama, E. (1999) Acta Neuropathol. (Berl.) 97, 260-266; Choi, J., Rees, H. D., Weintraub, S. T., Levey, A. I., Chin, L. S., and Li, L. (2005) J. Biol. Chem. 280, 11648-11655. There is also considerable evidence that fALS-causing mutations predispose SOD-1 to post-translational modifications, and that in vitro oxidative modification of SOD-1 induces aggregation Poon, H. F., Hensley, K., Thongboonkerd, V., Merchant, M. L., Lynn, B. C., Pierce, W. M., Klein, J. B., Calabrese, V., and Butterfield, D. A. (2005) Free Radic. Biol. Med. 39, 453-462; Andrus, P. K., Fleck, T. J., Gurney, M. E., and Hall, E. D. (1998) J. Neurochem. 71, 2041-2048; Tiwari, A., and Hayward, L. J. (2003) J. Biol. Chem. 278, 5984-5992; Zhang, H., Joseph, J., Crow, J., and Kalyanaraman, B. (2004) Free Radic. Biol. Med. 37, 2018-2026; Davies, K. J. (1987) J. Biol. Chem. 262, 9895-9901; and Rakhit, R., Cunningham, P., Furtos-Matei, A., Dahan, S., Qi, X. F., Crow, J. P., Cashman, N. R., Kondejewski, L. H., and Chakrabartty, A. (2002) J. Biol. Chem. 277, 47551-47556.